Parathyroid hormone (PTH) stimulates both bone formation and resorption. IGF-I plays a critical role in both of these actions of PTH. The ability of PTH to stimulate bone resorption is mediated primarily by induction of RANKL and suppression of OPG by osteoblasts resulting in the differentiation and subsequent activation of osteoclast precursors. However, deletion of the IGF-I receptor (IGF-IR) from osteoclast precursors blocks their ability to form mature osteoclasts and prevents this response to PTH. The mechanisms by which PTH stimulates bone formation are less well understood, but our data indicate that IGF-I signaling in osteoblasts is critical this anabolic role of PTH as well. We propose two models by which this may occur. The mature osteoblast centric model postulates that PTH stimulates IGF-I production by mature osteoblasts, and the IGF-I so produced then promotes the proliferation and differentiation of osteoprogenitors, enables terminal differentiation of the osteoblast, and permits osteoclast precursors to respond to the osteoclastogenic factors elaborated by the mature osteoblast. The osteoprogenitor centric model postulates that the osteoprogenitor responds directly to PTH including induction of IGF-I production. The IGF-I so produced mediates the ability of PTH to promote proliferation and differentiation of the osteoprogenitor as well as promoting the terminal differentiation of the osteoblast and its role in inducing osteoclastogenesis. In each model we postulate that the osteoclast plays an important role in facilitating the ability of PTH to promote osteoblast proliferation and differentiation. These models are not mutually exclusive. To test these models we have developed mice in which IGF-I or its receptor are selectively deleted from osteoclasts or osteoblasts at different stages of maturity. These mouse lines will enable us to determine which cells are required to produce and respond to IGF-I in a manner regulated by and necessary for the skeletal actions of PTH. The hypothesis to be tested is the following. Hypothesis: IGF-I signaling is critical for both the anabolic and catabolic actions of PTH on bone. The balance between the anabolic and catabolic actions of PTH depends on the production of and response to IGF-I by the different cells in the osteoblast and osteoclast lineages, responses which vary by cell type and duration of exposure to PTH. This hypothesis will be tested by achieving the following aims. Aim 1: Determine whether production of and response to IGF-I by osteoclasts and osteoblasts at different stages of maturation differentially regulates the balance between bone formation and bone resorption. Aim 2: Determine whether the maturity of the osteoblast that produces or responds to IGF-I alters the balance in the anabolic and catabolic actions of PTH. Aim 3: Determine whether IGF-I signaling in osteoclasts is critical for the balance of anabolic and catabolic actions of PTH. Clinical significance: PTH provides treatment for osteoporosis. However, PTH has both anabolic and catabolic actions on bone. Knowing the role of IGF-I in these actions of PTH should enhance its rational use. PUBLIC HEALTH RELEVANCE: Parathyroid hormone (PTH) is an important means of treating osteoporosis, but it stimulates both bone formation and bone resorption. Insulin like growth factor-I (IGF-I) mediates these actions of PTH, and may be useful to enhance the bone forming actions of PTH. This proposal will investigate this potential by examining the role of IGF-I signaling in those cells stimulated by PTH to form new bone.